The Year in FDA Approvals

Wednesday, May 1, 2019

In the past year, the U.S. Food and Drug Administration (FDA) approved several therapies for the treatment of myeloid malignancies, including the first treatment approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN). Here, we review the regulatory approvals since our last “Focus on Myeloid Malignancies” special edition published in May 2018.

Ivosidenib

On July 20, 2018, the FDA approved ivosidenib, a small-molecule IDH1 inhibitor, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) and an IDH1 mutation. This is the first IDH1 inhibitor approved for this indication, and the agent was approved simultaneously with the RealTime IDH1 assay, a companion diagnostic designed to detect the IDH1 mutation.

The FDA based its approval decision on data from a single-arm study that evaluated the efficacy of ivosidenib in 174 patients with relapsed or refractory IDH1-mutated AML. After a median follow-up of 8.3 months (range = 0.2-39.5 months), 32.8 percent of patients experienced complete remission (CR) or CR with partial hematologic recovery (CRh). The median time to response was 2.0 months (range = 0.9-5.6 months), and responses lasted for a median of 8.2 months (range = 5.6-12 months).

In addition, of the 110 participants who were red blood cell (RBC) or platelet transfusion–dependent at baseline, 41 (37.3%) went at least 56 days without requiring a transfusion after ivosidenib treatment.

Ivosidenib was approved through the priority-review pathway and with fast-track and orphan-product designations. Studies of ivosidenib in combination with other therapies and in newly diagnosed AML are ongoing.

Glasdegib

On November 23, 2018, the FDA approved glasdegib, in combination with low-dose cytarabine, for patients with newly diagnosed AML who are age 75 or older or who have comorbidities that preclude the use of intensive induction chemotherapy.

The agency’s decision was based on results from the multicenter, open-label BRIGHT AML 1003 study, which included 115 patients with AML who met at least one of the following criteria: aged 75 years or older, severe cardiac disease, Eastern Cooperative Oncology Group performance status score of 2, or baseline serum creatinine >1.3 mg/dL.

Glasdegib was approved through the priority-review pathway and was granted orphan-product designation. Studies of glasdegib in combination with agents other than low-dose cytarabine, including DNA hypomethylating agents, are ongoing.

Venetoclax

On November 23, 2018, the FDA approved the BCL2 inhibitor venetoclax, in combination with azacitidine or decitabine or low-dose cytarabine, for the treatment of patients with newly diagnosed AML who are age 75 or older or who have comorbidities that preclude use of intensive induction chemotherapy.

The approval is based on results from two phase II trials: the M14-358 and M14-397 studies.

The M14-358 study evaluated venetoclax in combination with azacitidine (n=67) or decitabine (n=13) in patients with newly diagnosed AML. Twenty-five patients who received venetoclax plus azacitidine achieved a CR, with a median duration of remission of 5.5 months (range = 0.4-30 months). Seven of the patients who received venetoclax plus decitabine achieved a CR, with a median duration of remission of 4.7 months (range = 1.0-18 months).

The M14-387 study evaluated venetoclax in combination with low-dose cytarabine in patients with newly diagnosed AML (n=61), including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. When combined with low-dose cytarabine, treatment with venetoclax induced CR in 13 patients, with a median observed remission duration of six months (range = 0.03-25 months).

On November 28, 2018, the FDA approved gilteritinib, an oral FLT3/AXL inhibitor, for the treatment of adult patients with FLT3-mutated relapsed or refractory AML. The FDA also expanded the indication for the LeukoStrat CDx FLT3 Mutation Assay, a companion diagnostic to detect the FLT3 mutation.

The agency’s decision was based on interim results from the phase III ADMIRAL trial, which enrolled 138 patients with relapsed or refractory AML and a confirmed FLT3 mutation.

Gilteritinib was administered orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. After a median follow-up of 4.6 months (range = 2.8-15.8 months), 29 gilteritinib-treated patients (21%) achieved CR or CRh. Of the 106 patients who were RBC or platelet transfusion–dependent at the start of treatment with gilteritinib, 33 (31.1%) became transfusion-independent during any 56-day, postbaseline period.

The most common AEs (occurring in ≥20% of patients) included myalgia/arthralgia, fatigue, and liver transaminase elevation.

Gilteritinib was approved through fast-track and priority-review pathways and received orphan-product designation. Studies of gilteritinib in combination with chemotherapy or as maintenance therapy after allogeneic hematopoietic cell transplantation are ongoing.

Tagraxofusp-erzs

On December 21, 2018, the FDA approved tagraxofusp-erzs (formerly SL-401), a CD123-directed cytotoxin, for the treatment of adults and children (≥2 years of age) with blastic plasmacytoid dendritic cell neoplasm (BPDCN). This marks the first approval for this rare disease.

The efficacy of tagraxofusp-erzs was evaluated in two cohorts of patients in a single-arm clinical trial. In the first cohort, which included 13 patients with untreated BPDCN, seven (53.8%) achieved a CR or CR with a skin abnormality not indicative of active disease (CRc). The median response duration was not reached in this cohort. In the second cohort, which included 15 patients with relapsed or refractory BPDCN, one patient each achieved a CR (which lasted for 111 days) and a CRc (which lasted for 424 days).

The most common clinical AEs (occurring in ≥30% of patients) associated with tagraxofusp-erzs included capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia, chills, and weight increase. The most commonly observed laboratory abnormalities (identified in ≥50% of patients) were decreases in lymphocytes, albumin, platelets, hemoglobin, and calcium, as well as increases in glucose and liver enzymes. Given this observation, the approval letter advises health-care providers to monitor patients’ liver enzyme levels and ensure an albumin level ≥3.5 g/dL before starting therapy.

Tagraxofusp-erzs was approved with a boxed warning about the increased risk of capillary leak syndrome, which may be life-threatening or fatal.

This agent was approved through the priority-review pathway and was granted breakthrough therapy and orphan-product designations. Studies of tagraxofusp-erzs in other myeloid malignancies are ongoing.

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